Blood：PTPN22激活AKT促进白血病细胞生存

磷酸酶PTPN22多态性变异已与多种自身免疫性疾病风险增加有关。近日，一项刊登在Blood杂志上的研究表明，PTPN22在慢性淋巴细胞白血病（CLL）中也过度表达。

慢性淋巴细胞白血病属慢性淋巴细胞恶性克隆性疾病。多起源于B细胞的恶性转化，淋巴细胞分化受阻于未成熟阶段，易伴发自身免疫病和低丙球蛋白血症。

研究证实，过度表达的PTPN22通过阻断B细胞受体（BCR）负调控细胞生存的信号通路，显著抑制抗原诱导的早期白血病细胞凋亡。更重要的是，该研究发现 PTPN22正向调节抗凋亡激酶Akt，Akt提供一个强大的刺激信号促进抗原诱导的白血病细胞生存。

总的来说，这些数据表明，PTPN22过度的表达对白血病细胞来说是一种保护机制，能使自身抗原激活的白血病细胞逃避死亡，提示蛋白激酶PKC抑制剂作用于PTPN22可用于治疗白血病。

doi:10.1182/blood-2012-01-403162
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Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT

Roberto Negro, Stefania Gobessi, Pablo G. Longo, Yantao He, Zhong-Yin Zhang, Luca Laurenti, and Dimitar G. Efremov

A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes. We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells. This selective uncoupling of AKT from other downstream BCR signaling pathways is a result of inhibition of a negative regulatory circuit involving LYN, CD22, and SHIP. Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli. Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.